Receptor tyrosine kinases (RTKs) are typically activated through a precise sequence of intracellular phosphorylation events starting with a tyrosine residue on the activation loop (A-loop) of the kinase domain (KD). From this point the mono-phosphorylated enzyme is active, but subject to stringent regulatory mechanisms which can vary dramatically across the different RTKs. In the absence of extracellular stimulation, fibroblast growth factor receptor 2 (FGFR2) exists in the mono-phosphorylated state in which catalytic activity is regulated to allow rapid response upon ligand binding, whilst restricting ligand-independent activation. Failure of this regulation is responsible for pathologic outcomes including cancer. Here we reveal the molecular mechanistic detail of KD control based on combinatorial interactions of the juxtamembrane (JM) and the C-terminal tail (CT) regions of the receptor. JM stabilizes the asymmetric dimeric KD required for substrate phosphorylation, whilst CT binding opposes dimerization, and down-regulates activity. Direct binding between JM and CT delays the recruitment of downstream effector proteins adding a further control step as the receptor proceeds to full activation. Our findings underscore the diversity in mechanisms of RTK oligomerisation and activation.
Bibliographical noteKAUST Repository Item: Exported on 2023-07-18
Acknowledgements: This work was funded in part by CRUK grant C57233/A22356 awarded to J.E.L. The research by S.T.A. supported by funding from King Abdullah University of Science and Technology (KAUST). Z.A. is supported by National Institutes of Health (NIH) grant R01 CA200231 and Cancer Prevention Research Institute of Texas (CPRIT) grant RP180813. We acknowledge SOLEIL for provision of synchrotron radiation facilities (proposals nr. 20181104 and 20190107) and we would like to thank J. Perez and A. Thureau for assistance in using the beamline SWING. We thank A. Stainthorp for helpful discussion and comments. We thank Dr A. Kalverda (The Astbury Structural Biology Laboratory, University of Leeds) for the help on NMR data collection and analysis.